We have developed a novel two element procedure for transplantation tolerance induction that does not require immunosuppression. With it, we have achieved permanent survival of fully allogeneic islet grafts, and prolonged survival of islet xenografts in rodents. This Program Project seeks to use this new information as a point of departure for making islet transplantation without immunosuppression a viable therapeutic option for persons with diabetes mellitus. Our specific goals are these: 1. To perfect methods for inducing permanent allogeneic and xenogeneic islet graft tolerance in both rodent and human immune systems by means of a two element therapy comprised of donor spleen cells and short term treatment with antibody directed against CD4O ligand (CD4OL). 2. To gain comprehensive understanding of the molecular, biochemical, and cellular mechanisms by which this tolerant state is achieved and maintained. The observations we have published to date suggest that our procedure induces tolerance by presenting antigen in the absence of co-stimulation. We believe that understanding this process at the molecular, biochemical, and cellular levels will reveal general principles of tolerance induction that can then be developed into a clinically applicable transplantation procedure. The Program Project format affords the promise of generating a more comprehensive understanding of T cell activation and tolerance induction than could be achieved by individual investigators working in isolation. Project #1 is directed at understanding the cellular mechanisms responsible for the state of unresponsiveness in allograft tolerance. Project #2 has parallel goals in understanding the unique problems posed by xenograft tolerance induction in both the mouse immune system and the human immune system in lymphohemopoietic chimeric scid mice. The contribution of the newly recognized regulation of antigen presenting cell (APC) maturation by CD4O in the development of an immune response to transplantation antigens is the subject of Project #3. Understanding the molecular signaling pathways utilized by CD4O is the subject of Project #4. Three Core Facilities will facilitate the work of these Projects. The Islet Core Facility (Core A) will provide the principal tissue to be transplanted. The Animal Core (Core B) will provide specialized husbandry, breeding, testing, and specialty surgical services. The Transgenic Core (Core C) will develop genetic mutants for the analysis of mechanism. If our goal can be reached, we will gain not only a deeper understanding of the molecular, biochemical, and cellular mechanisms of CD4O-CD4OL interaction, but also the ability to translate this information into a practical method of islet transplantation tolerance induction for the cure of diabetes.